1. Field of the Invention
The present invention relates to the field of fungicidal compositions and methods. More particularly, the present invention concerns novel fungicidal heterocyclic aromatic amides and methods involving application of fungicidally effective amounts of such compounds to the locus of a plant pathogen. The present invention also concerns methods useful in the preparation of heterocyclic aromatic amides and their fungicidal compositions.
2. Description of the Prior Art
A variety of antifungal compositions and methods are well known in the art. Antimycin, for example, has been identified as a naturally occurring substance produced by Streptomryces spp. with antibiotic properties (Barrow, C. J.; et al., Journal of Antibiotics, 1997, 50(9), 729). These substances have also been found to be effective fungicides (The Merck Index, Twelfth Edition, S. Budavari, Ed., Merck and Co., Whitehouse Station, N.J., 1996, p. 120). WO 97/08135 describes acylaminosalicylic acid amides which are useful as pesticides. EP-A-0-661269 discloses substituted heterocyclic carboxylic acid amides useful as medical drugs. JP-A-7-233165 discloses antifungal dilactones having 3-hydroxypyridinecarboxyl groups with antimycotic action. The iso-butyryl, tigloyl, iso-valeryl and 2-methylbutyryl derivatives of these latter compounds are further described in the following references: Tetrahedron 1998, 54, 12745-12774; J. Antibiot. 1997, 50(7), 551; J. Antibiot. 1996, 49(7), 639; J. Antibiot. 1996, 49(12), 1226; and Tetrahedron Lett. 1998, 39, 4363-4366.
However, there has remained a need for new fungicides. The present invention provides fungicides which have a high residual activity, greater activity at lower application rates, curative activity, and a broader spectrum of efficacy.
Briefly describing one aspect of the present invention, there are provided compounds comprising heterocyclic aromatic amides (HAA) of the Formula I: 
wherein X1-X4, M, Z, and A are hereafter defined. The invention also encompasses hydrates, salts and complexes thereof.
The present invention also provides fungicidal compositions comprising the HAA in combination with phytologically acceptable carriers and/or diluents. Methods for the use of the heterocyclic aromatic amide compounds and compositions are also disclosed.
It is an object of the present invention to provide HAA and compositions thereof which are effective as antifungal agents.
Another object of the present invention is to provide methods for the control and/or prevention of fungal infestations, which methods include the application of HAA and compositions containing same.
Further objects and advantages of the present invention will be apparent from the description which follows.
The present invention relates to various HAA compounds which are active as antifungal agents. Also included are formulations including the HAA compounds, and methods of using the HAA compounds and formulations. The methods of preparing the HAA compounds are also encompassed by the present invention and their method of preparation and use as fungicides.
The novel antifungal HAA compounds of the present invention are described by the following Formula I: 
wherein:
a. 
xe2x80x83represents a 5- or 6-membered heterocyclic aromatic ring in which
(i) each of X1-X4 is independently O, S, NRxe2x80x2, N, CRxe2x80x3 or a bond;
(ii) no more than one of X1-X4 is O, S or NRxe2x80x2;
(iii) no more than one of X1-X4 is a bond;
(iv) When any one of X1-X4 is S, O or NRxe2x80x2, one of the adjacent X1-X4 must represent a bond; and
(v) at least one of X1-X4 must be O, S, NRxe2x80x2 or N;
xe2x80x83wherein
Rxe2x80x2 is H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, hydroxy, acyloxy, C1-C6 alkoxymethyl, CHF2, cyclopropyl or C1-C4 alkoxy; and Rxe2x80x3 is independently H, halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, aryl, C1-C3 NHC(O)alkyl, NHC(O)H, C1-C3 haloalkylthio, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl or nitro wherein adjacent Rxe2x80x3 substituents may form a ring or adjacent Rxe2x80x2 and Rxe2x80x3 substituents may form a ring;
b) Z is O, S or NORZ in which RZ is H or C1-C3 alkyl; and
c) A represents
(i) C1-C14 alkyl, C2-C14 alkenyl, or C2-C14 alkynyl, all of which may be branched or unbranched, unsubstituted or substituted with halogen, hydroxy, nitro, aroyl, aryloxy, C1-C8 acyloxy, C1-C6 alkylthio, arylthio, aryl, heteroaryl, heteroarylthio, heteroaryloxy, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy,
(ii) C3-C14 cycloalkyl, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, cyano, nitro, aroyl, aryloxy, heteroaryloxy, C1-C6 alkylthio, arylthio, heteroarylthio, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C8 acyloxy, aryl, heteroaryl, C1-C6 acyl, carboaryloxy, carboheteroaryloxy, C1-C6 carboalkoxy or amido unsubstituted or substituted with one or two C1-C6 alkyl groups,
(iii) C6-C14 bi- or tricyclic ring system, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, cyano, nitro, aroyl, aryloxy, heteroaryloxy, C1-C6 alkylthio, arylthio, heteroarylthio, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C8 acyloxy, aryl, heteroaryl, C1-C6 acyl, carboaryloxy, carboheteroaryloxy, C1-C6 carboalkoxy or amido unsubstituted or substituted with one or two C1-C6 alkyl groups,
(iv) aryl or heteroaryl, which may be unsubstituted or substituted with nitro, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, carboaryloxy, carboheteroaryloxy, C1-C6 carboalkoxy or amido unsubstituted or substituted with one or two C1-C6 alkyl groups, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 OC(O)alkyl, OC(O)aryl, C3-C6 OC(O)cycloalkyl, C1-C6 NHC(O)alkyl, C3-C6 NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, C3-C6 cycloalkylthio, C3-C6 cycloalkylsulfonyl, C3-C6 cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)RY, C(NORX)RY, in which any alkyl or cycloalkyl containing substituent may be substituted with one or more halogens and in which any aryl or heteroaryl containing substituent may also be unsubstituted or substituted with halogen, cyano, nitro, aroyl, aryloxy, aryl, heteroaryl, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 carboalkoxy or amido unsubstituted or substituted with one or two C1-C6 alkyl groups, where RY and RX are independently H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, aryl or heteroaryl, and
(v) 
where *=point of attachment
in which
Q1, Q2 are O or S;
W is O, CH2, CHR6, or a bond;
R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl or heteroaryl;
R2 is H, C1-C3 alkyl, C2-C5 alkenyl or C2-C5 alkynyl;
R3 is H, R1, OR1, OC(O)R1, OC(O)OR1 or OC(O)NR1R6;
R4 and R5 are independently H, C1-C6 alkyl, or C2-C6 alkenyl, provided that the sum of carbons for R4 plus R5 is six or less, and further provided that R4 and R5 may be joined into a C3-C6 ring;
R6 and R7 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl or C2-C5 alkynyl provided that at least one of R6 and R7 is H;
with the proviso that when 
wherein
Rxe2x80x3 is H or OCH3, then
R1 is not isobutyryl, tigloyl, isovaleryl, or 2-methylbutanoyl;
d) M represents
H, Si(t-Bu)Me2, Si(Ph)Me2, SiEt3, SiMe3, C(Z)R8, SO2R9 where R8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, alkoxyalkyl, haloalkyl, alkoxyalkenyl, haloalkenyl, alkoxyalkynyl, haloalkynyl, substituted and unsubstituted arylalkyl, substituted and unsubstituted arylalkenyl, substituted and unsubstituted arylalkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C1-C6 haloalkoxy, C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 haloalkynyloxy, C1-C6 thioalkoxy, substituted and unsubstituted arylalkoxy, substituted and unsubstituted arylalkenyloxy, substituted and unsubstituted arylalkynyloxy, substituted and unsubstituted aryloxy, substituted and unsubstituted heteroaryloxy, amino unsubstitued or substituted with one or two C1-C6 alkyl groups, and R9 is C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, aryl, or heteroaryl.
The terms alkyl, alkenyl, alkynyl and the like, as used herein, include within their scope both straight and branched groups; the terms alkenyl, alkenylene and the like are intended to include groups containing one or more double bonds; and the terms alkynyl, alkynylene and the like are intended to include groups containing one or more triple bonds. Cycloalkyl, as used herein, refers to C3-C14 cycloalkyl groups containing 0-3 heteroatoms and 0-2 unsaturations. Bi- or tricyclic ring systems refers to C6-C14 aliphatic ring systems containing 0-3 heteroatoms and 0-2 unsaturations. The foregoing terms further contemplate either substituted or unsubstituted forms. Unless specifically defined otherwise, a substituted form refers to substitution with one or more groups selected from halogen, hydroxy, cyano, nitro, aroyl, aryloxy, aryl, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, C1-C8 acyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, carboaryloxy, carboheteroaryloxy, C1-C6 carboalkoxy or amido unsubstituted or substituted with one or two C1-C6 alkyl groups. All of the above terms and definitions assume that the rules of chemical bonding and strain energy are satisfied.
The term aryl as used herein refers to a substituted phenyl or naphthyl group. The term heteroaryl refers to any 5 or 6 membered aromatic ring containing one or more heteroatoms; these heteroaromatic rings may also be fused to other aromatic systems. The foregoing terms further contemplate either substituted or unsubstituted forms. A substituted form refers to substitution with one or more groups selected from nitro, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 OC(O)alkyl, OC(O)aryl, C3-C6 OC(O)cycloalkyl, C1-C6 NHC(O)alkyl, C3-C6 NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, C3-C6 cycloalkylthio, C3-C6 cycloalkylsulfonyl, C3-C6 cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)RY, C(NORX)RY where RY and RX are independently H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, aryl or heteroaryl in which any alkyl or cycloalkyl containing substituent may be substituted with one or more halogens and provided that the rules of chemical bonding and strain energy are satisfied.
The terms halogen and halo as used herein include chlorine, bromine, fluorine and iodine. The terms haloalkyl and the like refer to groups substituted with one or more halogen atoms.
The term Me as used herein refers to a methyl group. The term Et refers to an ethyl group. The term Pr refers to a propyl group. The term Bu refers to a butyl group. The term Ph refers to a phenyl group. The term EtOAc refers to ethyl acetate.
The term alkoxy as used herein refers to a straight or branched chain alkoxy group. The term haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
The term heteroatom as used herein refer to O, S and N.
The preferred 5- or 6-membered heterocyclic aromatic rings of the formula 
include the appropriate isomers of pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, and thiadiazole. The most preferred heterocyclic aromatic rings are pyridine, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, thiadiazole, and oxazole. Particularly preferred compounds of Formula I are based upon 2-amido-3-hydroxypyridine, 2-amido-3-hydroxy-4-methoxypyridine, 2-amido-3-hydroxypyrazine, and 4-amido-5-hydroxypyrimidine.
It will be appreciated that certain combinations of substituent groups for compounds which fall within the definitions given herein will be impossible to prepare for steric and/or chemical reasons. Such compounds are not included within the scope of the invention.
Various hydrates, salts and complexes of compounds of Formula I can be made in the conventional ways. For example, salts may be formed by replacing the hydroxyl hydrogen atom (M=H) with a cation, for example NH4+, +N(Bu)4, K+, Na+, Ca2+, Li+, Mg2+, Fe2+, Cu2+, etc. These derivatives are also useful in accordance with the present invention.
Throughout this document, all temperatures are given in degrees Celsius (xc2x0 C.) and all percentages are weight percentages, unless otherwise stated. The term ppm refers to parts per million. The term psi refers to pounds per square inch. The term m.p. refers to melting point. The term b.p. refers to boiling point.